Understanding How the Brain Reacts to Lows

OccupationEndocrinology Researcher, Washington University in St. Louis

FocusHypoglycemia

ADA Research FundingClinical Translational Award

Hypoglycemia is a familiar concern to too many people with diabetes. When the body's blood glucose dips too low, the results can range from hunger to dizziness, headaches, confusion—or worse.

The mechanics are seemingly simple. Glucose, or sugar, is "the fuel for the brain," says Philip Cryer, MD, a diabetes researcher at Washington University in St. Louis. Too little glucose in the blood means the brain runs out of gas. The symptoms of hypoglycemia, like shakiness or sweating, are the body's warning light, an urgent demand for sugar. When the brain's fuel runs out completely, the result is unconsciousness, coma, and even death.

The scariest thing about hypoglycemia is that even the best-managed blood glucose can go south all of a sudden. "The average type 1 diabetes patient has untold numbers of incidents over the course of a lifetime," Cryer says. "It's a very common problem." Common enough that people with type 1 diabetes are trained to recognize the signs. For most, it's just another challenge of living with diabetes: feel a low coming on (and test to confirm, if possible), and reach for a glass of juice, a handful of crackers, or glucose tablets.

Yet Cryer, who has been studying the surprisingly complex causes and effects of hypoglycemia for more than 20 years, argues that hypoglycemia is far more than an inconvenience and hasn't gotten the attention it's due. "There's a lot of denial. It's important that we at least understand it's an important clinical problem for people with diabetes," Cryer says. "Hypoglycemia is a very real thing."

Not only can hypoglycemia be fatal—Cryer says that anywhere between 2 and 10 percent of people with type 1 diabetes die as the result of a severe hypoglycemic event—but research has revealed that the effects of hypoglycemia are cumulative. "Episodes of hypoglycemia impair the body's defenses against future episodes," Cryer says.

They also alter the body's response to hypoglycemia. Hypoglycemic episodes take a toll on what's called the sympatho-adrenal response—the reactions in the brain that trigger the "warning light" of hypoglycemia symptoms to switch on. "Normally, when blood sugar goes down, there's an increase in activity in the sympatho-adrenal system," Cryer says.

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Over time, the body's overt response gets less and less dramatic—both in terms of its regulation of glucose levels and in terms of the signals it gives in response to falling glucose. Eventually, the "warning light" may not switch on at all, a condition known as hypoglycemia unawareness. "People don't always feel the warning signs, and that means they may not know to eat and break up an episode," Cryer says. By the time one comes on, it may be too late: For people with hypoglycemia unawareness, the first sign of an episode may be unconsciousness.

With support from the American Diabetes Association, Cryer and a team of researchers at Washington University are exploring the different facets of the brain's response to hypoglycemia. "We're trying to figure out why the sympatho-adrenal response is attenuated," or decreased, Cryer says. "We're pursuing the theory that there's a cerebral network that controls all this and goes awry in people with progressive hypoglycemia."

To find out what's happening, Cryer takes volunteers and puts them in a positron emission tomography (PET) scanner, a huge device that can monitor what's happening in the brain in real time. To streamline the studies, Cryer uses volunteers without diabetes. "I can induce hypoglycemia in healthy folks, and it's much more efficient to study it that way," he says. "It's not practical to have all this equipment sitting around waiting for a hypoglycemic attack." Using nondiabetic volunteers also helps ensure that whatever's going on in the brain is a reaction to the hypoglycemia and nothing else.

Cryer induces a hypoglycemic episode, then watches which part of the brain lights up in response using water that's been altered to make it slightly radioactive and hence visible to the PET scanner. So far, the most active part is the thalamus, a structure about 2 inches long located deep inside the brain. It plays a role in everything from regulating sleep to sensation.

That, Cryer says, suggests that people prone to hypoglycemia—people with type 1 and type 2 diabetes who must be treated with insulin—might have an "abnormality" in the thalamus that makes hypoglycemic episodes more likely and thwarts the brain's efforts to send out a warning when one is coming on.

Knowing where the problem occurs is still a long way from finding a cure, but it's a step forward. Grants from the ADA have helped Cryer train younger researchers who will be able to continue studying hypoglycemia for years to come. "I don't think we know enough to talk about a treatment," Cryer says. "But we have to keep doing research and figure out what's causing all this and how to prevent it."